The major goal of the last funding period was to use a glial-specific transgenic mouse model, the RCAS-tv-a system, to functionally determine the oncogenic role of insulin-like growth factor binding protein 2 (IGFBP2), which was identified from our genomic profiling studies as a marker for high-grade gliomas. We have achieved this goal, and for the first time discovered that IGFBP2 is a novel oncogene that, when combined with K-ras or platelet-derived growth factor beta (PDGFB), leads to the development and progression of two major types of glioma (astrocytoma and oligodendroglioma) (Dunlap et al., 2007). Our in vivo and ex vivo studies revealed that IGFBP2 activates the Akt pathway, and that pharmacological inhibition of Akt blocks IGFBP2-mediated cell viability. This finding is supported by recent data from Charles Sawyers' group showing that IGFBP2 over-expression in glioblastoma and prostate cancer is associated with PTEN mutation and PI3K/Akt activation (Mehrian-Shai et al., 2007). Our recent studies have shown that IGFBP2 activates the expression of VEGF and promotes angiogenesis. In this R01 renewal, we will test our hypothesis that IGFBP2 is important for glioma maintenance and that IGFBP2, in combination with the loss of PTEN, most efficiently activates the Akt and angiogenesis pathways, and results in progression of gliomas to glioblastoma. We will use our established RCAS system together with a Tet-inducible RCAS system for these studies. Our specific aims are the following. Specific aim 1. To determine the role of IGFBP2 over-expression in the maintenance of high grade gliomas. Specific aim 2. To determine which of the three Akt family members (Akt1, Akt2, and Akt3) is most important for glioma development and progression. Specific aim 3. To determine the cooperation of oncogene over-expression with PTEN inactivation to promote GBM. Specific aim 4. Effect of IGFBP2 expression on Akt and VEGF pathway therapeutics. PUBLIC HEALTH RELEVANCE: The significance of this study is to understand the mechanism and potentially key signaling pathways (Akt and VEGF) of a newly recognized oncogene of glioma, insulin-like growth factor binding protein 2 (IGFBP2) in maintenance of high-grade glioma and the crosstalk between IGFBP2 signaling pathway and inactivation of PTEN tumor suppressor gene. This in-depth understanding will provide insight in the development of targeted therapeutics for high-grade gliomas.